The proposed studies are designed to examine two aspects of the role of the endothelium in the cerebral circulation: permeability of the blood-brain barrier (BBB) and modulation of vasular responses by the endothelium. Experiments that I have completed suggest that veins are the primary site of disruption during acute hypertension, and disruption of the BBB in veins is associatd with, and presumably due to, increases in pial venous pressure. Experiments that are proposed will determine whether 1) rate of rise in venous pressure affects disruption of the BBB, 2) increases in venous pressure or magnitude of venous pressure mediate disruption of the BBB, and 3) severity of disruption of the BBB is similar in an open and closed window preparation. Studies in other vascular beds implicate a role for pulse pressure in the myogenic control of vascular tone. Pulsatile pressure and flow release prostaglandins and endothelium-derived relaxing factor (EDRF). Thus, alterations in pulse pressure may modulate endothelium dependent responses of cerebral arterioles. I plan to determine effects of 1) pulsatile pressure on cerebral arterioles, and determine the role of prostaglandins and EDRF in control of vascular tone during changes in pulse pressure, and 2) pulse pressure in disruption of the BBB in venules during hypertension. Hypertensive encephalopathy may be related to passive segmental dilation of cerebral arterioles, i.e., "sausage stringing." In chronically hypertensive rats, we have observed sausage string in cerebral arterioles. The proposed experiments will determine whether 1) sausage string occurs at the onset of, and presumably contributes to, hypertensive encephalopathy, and 2) focal dilation of cerebral arterioles during encephalopathy increases venous pressure and disrupts the BBB. Chroic hypertension also produces morphological and functional changes in vasular muscle and endothelium. Studies in using vessels from peripheral vascular beds have shown impaired endothelium-dependent vasodilatation in hypertensive animals. Preliminary experiments in vivo, which I have conducted, are the first to suggest that endothelium-dependent dilatation of cerebral arterioles is impaired in hypertensive rats. I plan to further investigate altered endothelium-dependent responses of cerebral arterioles during chronic hypertension. Impaired endothelium- dependent vasodilatation during hypertension may predispose to cerebral ischemia, and perhaps stroke.